Endocrine Abstracts (2002) 3 P179

Time dependency of somatotroph dysfunction following radiation damage of the hypothalamic-pituitary axis

K Darzy, E Ghigo & SM Shalet

Department of Endocrinology, Christie Hospital, Manchester, UK.

Radiation-induced growth hormone neurosecretory dysfunction (GHNSD) is, primarily, the result of radiation-induced hypothalamic damage. Consequently, reduced hypothalamic growth hormone releasing hormone (GHRH) secretion results in secondary somatotroph atrophy and attenuated peak GH responses to a bolus of exogenous GHRH. For the first time we have studied the presence of GHNSD and/or somatotroph atrophy in cranially irradiated adult survivors of childhood cancer. We have utilized two GH provocative tests; the Insulin Tolerance Test (ITT) as the 'Gold Standard' to assess hypothalamic pathways and the combined GHRH+AST to assess somatotroph integrity. In this test arginine is believed to inhibit hypothalamic somatostatin release allowing the GHRH to 'maximally' explore somatotroph GH reserve.

Both tests were performed in 50 adult patients, aged between 17 and 53 years, who had received cranial irradiation for non-pituitary brain tumours or leukaemia, and 26 matched normal controls. The ratio of the peak GH response to the GHRH+AST over that achieved with the ITT (Discordancy ratio) was used as a measure of the relative degree of hypothalamic damage versus pituitary atrophy. 26/50 patients had impaired responses to the ITT but 7 of the 26 'passed' the combined test; possibly suggesting the presence of GHNSD. The evolution of secondary pituitary atrophy with time accounts for this relatively low discordancy rate, which is also supported by the significant negative correlation between the peak GH response to the GHRH+AST and the time interval after irradiation (r = -0.34, p = 0.017).

The ratio also significantly correlated with the prolactin level (r = 0.45, p = 0.002), another marker of hypothalamic damage. In addition, the discordancy ratio was significantly higher (p= <0.0001) in patients (median 4.1, range 2-6.5) than normals (median 1.65, range 1.2-4). However, the ratio in patients irradiated more than 6 years previously approached that seen in normals.Furthermore, the ratio in those irradiated less than 6 years earlier was much higher (median 6, range 4-13) than in normals (p=0.0027) and those who had received radiotherapy more than 6 years previously (median 2.8, range 1.8-5, p=0.0038). There was a significant negative correlation between the discordancy ratio and the time interval after irradiation (r = -0.4, p=0.006).Collectively, these findings suggest that GH neurosecretory dysfunction is an early phenomenon following radiation injury to the h-p axis while secondary somatotroph atrophy evolves in subsequent years. It is possible that GHRH treatment can reverse secondary somatotroph atrophy and restore physiological GH secretion.

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